There are at present no disease-modifying treatments for Huntington's disease (HD) a highly complex neurodegenerative disorder caused by a polyglutamine repeat expansion within the gene encoding the Huntingtin (Htt) protein. Validated targets for therapeutic intervention in HD are currently limited to the HD gene transcript and its polypeptide product. The focus of this proposal is to explore a potential novel therapeutic target for HD, the histone demethylase SMCX/JARID1C. The impetus for this work comes from the study of expression of the gene encoding BDNF, a critical neurotrophic factor essential for survival of CNS neurons expressed in the cerebral cortex. The progressive depletion of BDNF and the decreased supply of BDNF to striatum through anterograde transport down corticostriatal axons is strongly implicated in neuropathology in HD. However, reductions in BDNF expression levels are only one aspect of the transcriptional dysregulation which characterizes the earliest phase of HD pathology. Other neuronal genes such as the dopamine receptor 2 (DRD2) and preproenkephalin (PPE) are reproducibly decreased in mRNA expression levels early in HD and the reduced expression of such transcripts other than BDNF may also be implicated in HD pathogenesis. We find that an epigenetic mark of active transcription, H3K4me3, is decreased at the BDNF promoter in cortex of HD mouse brain (R6/2). Furthermore, we find that a demethylase specific for H3K4me3, SMCX/JARID1C, is increased in levels in the cerebral cortex of R6/2 mice. We therefore hypothesize that increases in SMCX/JARID1C activity are a critical event in HD pathology and that effective therapeutic intervention in HD can be achieved through reductions in SMCX/JARID1C levels. This proposal is designed to gather data which test these hypotheses and provide a framework for the possible validation of SMCX/JARID1C as a target for therapeutic intervention in HD. Our specific aims are as follows: Aim 1) To perform a systematic genome wide analysis of the sites at which the H3K4me3 mark is altered in the pathological program modeling HD in the R6/2 mouse brain. Aim 2) Test the impact of acute knockdown of SMCX/JARID1C in mouse-derived primary neurons expressing mutant Htt. Aim 3) Test the impact of chronic reduction of SMCX/JARID1C levels on functional properties of mouse models of HD. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a devastating degenerative brain disease that inevitably leads to death. Current treatments do not change the course of the disease; therefore, a completely unmet medical need exists. The results of these studies will provide important preclinical data that will speak to the translational utility of targeting an enzyme that modifies DNA structure and transcription in HD systems.